As is known, carnitine possesses an asymmetrical carbon atom and the enantiomer L-carnitine is the isomer present in living organisms, where it is essential for fatty acid metabolism and functions actively in the transport of fatty acids across the mitochondrial membranes. For this reason L-carnitine, in addition to being a life-saving drug for those who suffer from an L-carnitine deficiency of genetic origin and to being used in cases of temporary L-carnitine deficiency, such as, for instance, those occurring after haemodialysis (U.S. Pat. No. 4,272,549, Sigma-Tau), plays an important role in energy metabolism and is regarded as a non-toxic natural product capable of enhancing cardiac function. It is therefore used as a support drug in the treatment of various heart diseases such as ischaemia, angina pectoris, arrhythmias, etc. (U.S. Pat. Nos. 4,649,159 and 4,656,191 Sigma-Tau). L-carnitine and its derivatives, moreover, have also been used to a significant extent as serum lipid lowering agents, anticonvulsants and blood product preservatives. Recently, one of its derivatives, propionyl L-carnitine (Dromos®), was launched on the Italian market for the treatment of intermittent claudication (U.S. Pat. No. 4,968,719, EP 0793962, Sigma-Tau).
There is also a substantially growing use of L-carnitine as a food supplement in the field of the so-called “health foods” or “nutraceuticals”.
All this explains why L-carnitine is produced industrially in large amounts and also why several attempts have been made to improve the industrial synthesis of L-carnitine in terms of the cost of the product.
From a general point of view, the synthesis pathways that can be used to synthesise L-carnitine are essentially three.
The first of these, starting from non-chiral or racemic compounds, passes through racemic intermediates, at the level of one of which the separation of the useful enantiomer occurs, with methods known to experts in pharmaceutical technology. Though this synthesis pathway presents the advantage of being able to rely on starting materials with a relatively low cost, for example, racemic carnitinamide (U.S. Pat. No. 4,254,053, Sigma-Tau); racemic 2,3-dichloro-1-propanol (N. Kasai and K. Sakaguchi, Tetrahedron Lett. 1992, 33, 1211); 3-butenoic acid (D. Bianchi, W. Cabri, P. Cesti, F. Francalanci, M. Ricci, J. Org. Chem., 1988, 53, 104); racemic 3-chloro-2-hydroxy-trimethylammonium chloride (R. Voeffray, J. C. Perlberger, L. Tenud and J. Gosteli, Helv. Chim. Acta, 1987, 70, 2058); racemic epichlorohydrin (H. Löster and D. M. Müller, Wiss. Z. Karl-Marx-Univ. Leipzig Math.-Naturwiss. R. 1985, 34, 212); diketene (L. Tenud, Lonza, DE 2,542,196, 2,542,227 and DE 2,518,813), it also presents a serious drawback, in that, at the moment one wishes to isolate the useful enantiomer from a racemic mixture, there is a theoretical loss of at least 50% of the product on which said separation is operated. In practice, then, the yields in this synthesis step are substantially lower (U.S. Pat. No. 4,254,053, Sigma-Tau) and there is the drawback of having to recover the chiral compound used for the separation of the racemic mixture.
The second synthesis pathway, again starting from non-chiral products, “creates” the chiral centre of the configuration desired, operating a synthesis step in a chiral environment, whether by means of a catalyst (H. C. Kolb, Y. L. Bennani and K. B. Sharpless, Tetrahedron: Asymmetry, 1993, 4, 133; H. Takeda, S. Hosokawa, M. Aburatani and K. Achiwa, Synlett, 1991, 193; M. Kitamura, T. Ohkuma, H. Takaya and R. Noyori, Tetrahedron Lett., 1988, 29, 1555), or by means of an enzyme (U.S. Pat. No. 4,707,936, Lonza). The disadvantages of this pathway are the high cost of the catalysts and the fact that, at the time the chiral centre is created catalytically, one is normally unable to obtain the pure enantiomer, but mixtures are obtained with variable enantiomeric excesses of the useful isomer, with all the consequent difficulties of having to separate two substances with the same physico-chemical characteristics. In the case of the use of micro-organisms in continuous-cycle reactors, the transformation of the starting products into end products is never complete and the end product has to be scrupulously purified of all organic impurities of cellular origin, which are dangerous in that they are potential allergens.
The third synthesis pathway involves the use of a chiral starting product, which is transformed into L-carnitine via a series of reactions which, if the chiral centre is affected, must be stereospecific, which means that the stereochemistry of said centre must be maintained or completely inverted during the reaction, which is not always easy to achieve. If, on the other hand, the synthesis step does not affect the chiral centre, the enantiomeric excess (ee) of the end product must be the same, or very close to, the starting product, which means that “racemising” reaction conditions must be carefully avoided. Another limitation is the cost of the chiral starting products, which is normally much higher than that of non-chiral products. The effect of these difficulties has been that none of the various processes starting from chiral products such as, for example, 1a R-(−)-epichlorohydrin (M. M. Kabat, A. R. Daniewski and W. Burger, Tetrahedron: Asymmetry, 1997, 8, 2663); D-galactono-1,4-lactone (M. Bols, I. Lundt and C. Pedersen, Tetrahedron, 1992, 48, 319); R-(−)-malic acid (F. B. Bellamy, M. Bondoux, P. Dodey, Tetrahedron Lett. 1990, 31, 7323); R-(+)-4-chloro-3-hydroxybutyric acid (C. H. Wong, D. G. Drueckhammer and N. M. Sweers, J. Am. Chem. Soc., 1985, 107, 4028; D. Seebach, F. Giovannini and B. Lamatsch, Helv. Chim. Acta, 1985, 68, 958; E. Santaniello, R. Casati and F. Milani, J. Chem. Res., Synop., 1984, 132; B. Zhou, A. S. Gopalan, F. V. Middlesworth, W. R. Shieh and C. H. Sih; J. Am. Chem. Soc., 1983, 105, 5925); 4-hydroxy-L-proline (P. Renaud and D. Seebach, Synthesis, 1986, 424); (−)-β-pinene (R. Pellegata, I. Dosi, M. Villa, G. Lesma and G. Palmisano, Tetrahedron, 1985, 41, 5607); L-ascorbic acid or arabinose (K. Bock, I. Lundt and C. Pederson; Acta Chem. Scand., Ser. B, 1983, 37, 341); D-mannitol (M. Fiorini and C. Valentini, Anic, EP 60.595), has to date been used for the industrial production of L-carnitine.
A case apart is the Sigma Tau Italian patent No. 1,256,705, which may be regarded as a mixture of the first and second synthesis pathways. What it describes, in fact, is the preparation of L-carnitine starting from D-(+)-carnitine, obtained as a discard product from the L-carnitine preparation process by resolution of the carnitinamide racemic mixture by means of camphoric acid (U.S. Pat. No. 4,254,053, Sigma-Tau).
The bibliographical and patent references cited above merely give some idea of the vast body of work carried out in order to find an economically advantageous synthesis of L-carnitine. The fact is that the only two processes which have proved industrially and economically valid are those used by the two main manufacturers of L-carnitine, Sigma-Tau and Lonza, as described in the two above-mentioned patents, U.S. Pat. Nos. 4,254,053 and 4,708,936, which date back to 1978 and 1987, respectively.